[First-line treatment of multiple myeloma]. / Primärtherapie beim Multiplen Myelom.

Within the last two decades the therapeutic options for newly diagnosed multiple myeloma have changed dramatically. The implementation of high-dose chemotherapy with melphalan and subsequent autologous blood stem cell transplantation initially led to prolonged survival in younger, fit patients. Furthermore, recent data suggest that patients with high-risk disease seem to benefit most from tandem transplantation approaches. Therefore, risk stratification at initiation of first-line treatment is of great importance. With the advent and integration of the so-called novel agents, such as thalidomide, lenalidomide and bortezomib into first-line treatment, both transplant eligible and ineligble patients gained new therapeutic perspectives. In Germany, the combination of bortezomib with cyclophosphamide and dexamethasone is currently considered the standard of care as induction regimen before high-dose treatment and transplantation; however, the combination of lenalidomide, bortezomib and dexamethasone is increasingly being used, but is still not yet approved in Germany. For patients where high-dose therapy and stem cell transplantation are not feasible, bortezomib and lenalidomide are available as backbone agents of various combination regimens. Recently, the anti-CD38 antibody daratumumab has been approved in combination with bortezomib, melphalan and prednisone as primary treatment for newly diagnosed patients. An allogeneic stem cell transplantation can be considered for younger patients without relevant comorbidities and with high-risk disease or early relapse after autologous blood stem cell transplantation but should only be performed within controlled clinical trials and in specialized centers.

Bortezomib improves outcome after SCT in multiple myeloma patients with end-stage renal failure.

Patients with multiple myeloma and dialysis-dependent renal failure have dismal outcomes. In this retrospective analysis of a case series, we evaluated 27 consecutive patients, all of whom required haemodialysis at the time of first-line induction therapy with either bortezomib or a standard regimen followed by high-dose chemotherapy and auto-SCT. The overall response rate was significantly better after bortezomib-based induction before auto-SCT (83% vs 36%, P=0.02) and at day +100 post auto-SCT (100% vs 58%, P=0.01). Bortezomib also prolonged EFS and furthermore, a trend towards a shorter time on haemodialysis was observed in the bortezomib group at a median of 6.1 months (0.2-68.2 months) vs 17.1 months (0.7-94.3 months, P=0.38) in patients who had received vincristine, adriamycin, dexamethasone or vincristine, adriamycin, dexamethasone-like induction regimens. These data demonstrate the superior efficacy of bortezomib-based induction therapy in transplant-eligible patients with end-stage renal failure.

Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma.

Osteolytic bone disease in multiple myeloma (MM) is caused by enhanced osteoclast (OCL) activation and inhibition of osteoblast function. Lenalidomide and bortezomib have shown promising response rates in relapsed and newly diagnosed MM, and bortezomib has recently been reported to inhibit OCLs. We here investigated the effect of lenalidomide on OCL formation and osteoclastogenesis in comparison with bortezomib. Both drugs decreased alpha V beta 3-integrin, tartrate-resistant acid phosphatase-positive cells and bone resorption on dentin disks. In addition, both agents decreased receptor activator of nuclear factor-kappaB ligand (RANKL) secretion of bone marrow stromal cells (BMSCs) derived from MM patients. We identified PU.1 and pERK as major targets of lenalidomide, and nuclear factor of activated T cells of bortezomib, resulting in inhibition of osteoclastogenesis. Furthermore, downregulation of cathepsin K, essential for resorption of the bone collagen matrix, was observed. We demonstrated a significant decrease of growth and survival factors including macrophage inflammatory protein-alpha, B-cell activating factor and a proliferation-inducing ligand. Importantly, in serum from MM patients treated with lenalidomide, the essential bone-remodeling factor RANKL, as well as the RANKL/OPG ratio, were significantly reduced, whereas osteoprotegerin (OPG) was increased. We conclude that both agents specifically target key factors in osteoclastogenesis, and could directly affect the MM-OCL-BMSCs activation loop in osteolytic bone disease.

Targeted treatments to improve stem cell outcome: old and new drugs.

Thalidomide, lenalidomide and bortezomib have been approved for the treatment of relapsed or refractory multiple myeloma in the recent years. These agents are now being increasingly integrated into therapeutic regimens for newly diagnosed patients. First data are available on the promising activity of these novel agents in induction therapy, as well as maintenance treatment to improve outcome after stem cell transplantation. Whether these early results will lead to prolonged overall survival and thereby ultimately redefine the role of stem cell transplantation in first-line treatment of multiple myeloma will be one of the most important questions to be answered in the coming years. Bone Marrow Transplantation (2007) 40, 1129-1137; doi:10.1038/sj.bmt.1705829; published online 3 September 2007.

Thalidomide in newly diagnosed multiple myeloma: influence of thalidomide treatment on peripheral blood stem cell collection yield.

In a phase III randomized, multicenter study, the German-speaking Myeloma-Multicenter Group (GMMG) and the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) group investigated the influence of thalidomide (Thal) on the outcome of peripheral blood stem cell (PBSC) collection in multiple myeloma (MM) before peripheral autologous blood stem cell transplantation (ABSCT). We analyzed the data of 398 myeloma patients after induction with Thal, doxorubicin and dexamethasone (TAD) in comparison with vincristine, doxorubicin and dexamethasone (VAD) followed by mobilization with cyclophosphamide, doxorubicin, dexamethasone (CAD) and PBSC collection. Within both the study groups, patients treated with TAD showed to collect significantly fewer CD34(+) cells compared with VAD (GMMG, TAD: median 9.8 x 10(6)/kg; range 2.0-33.6; VAD: median 10.9 x 10(6)/kg range 3.0-36.0; P=0.02) (HOVON, TAD: median 7.4 x 10(6)/kg; range 2.0-33.0; VAD: median 9.4 x 10(6)/kg; range 0.0-48.7; P=0.009). However, engraftment after peripheral autologous stem cell transplantation showed no difference between Thal and VAD groups. We conclude that Thal as a part of induction regimen is associated with better response rates (GMMG-HD3: CR/PR 79%, VAD: CR/PR 58%; HOVON-50: TAD: CR/PR 81%, VAD: CR/PR 61%), but significantly affects the yield of PBSC collection. Nevertheless, the number of total CD34(+) cells collected was sufficient for double autologous transplantation in 82% of the Thal patients, with at least 2.5 x 10(6)/kg CD34(+) cells.

Molecular monitoring of tumour load kinetics predicts disease progression after non-myeloablative allogeneic stem cell transplantation in multiple myeloma.

BACKGROUND: Non-myeloablative allogeneic stem cell transplantation followed by immunomodulatory therapies is considered a potentially curative approach in the treatment of multiple myeloma and most effective in a minimal residual disease setting. PATIENTS AND METHODS: The aim of this study was to find the most sensitive real-time PCR assay (TaqMan), based on the IGH rearrangement, to quantify the tumour load of 11 patients with multiple myeloma after non-myeloablative allogeneic transplantation. Patient-allele specific primers (ASO) and the TaqMan probe were derived from CDR2 and CDR3 hypervariable regions of IGH, while consensus primers were located within the FR3 and FR4/JH regions. Four different approaches of primer combinations were tested. RESULTS: ASO-forward and -reverse primers together with the clone-specific TaqMan probe were the most sensitive approach compared with the JH (P=0.071) or the FR3 consensus primer (P <0.001). The detection limit amounted to 1/10(4)-1/10(5) cells. Consecutively, 120 samples from 11 patients prior and post allogeneic transplantation were analysed. Three patients reached complete clinical remission accompanied by molecular remission. Disease progression or relapse was seen in six patients. In five, molecular progressive disease was detected prior to the clinical diagnosis of progression or relapse. CONCLUSION: Patient-specific real-time IGH-PCR provides the opportunity for earlier treatment intervention.